Age-related macular degeneration (AMD) is the leading cause of blindness among Americans over the age of 65 with the majority of visual loss attributable to the neovascular form of AMD. Current treatments are modestly effective but none have reliably improved visual outcomes. Recent studies have shown that ranibizumab (Lucentis(tm)), when injected every 4 weeks into the eye for 1 year, can stabilize visual acuity in 95% of patients and substantially improve vision in 34% of patients. Widespread implementation of this dosing schedule has obvious limitations and the cost of these repeated injections is expected to be high. Alternative dosing schedules have not been evaluated in large comparative clinical trials. Bevacizumab (Avastin(r)) is the monoclonal antibody from which Lucentis(tm) was derived. Anecdotal evidence to date suggests that intravitreal Avastin(r) may also be effective for the treatment of neovascular AMD. It is available for off-label use and has been adopted as a first line therapy for neovascular AMD by many retina specialists, despite the absence of any randomized clinical trial data to support its intraocular use. In addition, a number of drugs when combined with Avastin(r) or Lucentis(tm), have the potential to improve visual outcomes but have not been evaluated in large clinical trials. In this application, we propose two consecutive multi-center, randomized clinical trials to be known as the Comparison of AMD Treatment Trials (CATT). The specific aim of the first trial (Monotherapy Trial) will be to determine the relative safety and efficacy of the following treatments for neovascular AMD in 1230 patients: 1) Lucentis(tm) on a fixed dosing schedule, 2) Lucentis(tm) on indication (variable dosing schedule driven by clinical response to treatment), or 3) Avastin(r) on indication. The primary outcome measure will be change in visual acuity. Secondary outcomes will include number of treatments, anatomical changes on OCT and fluorescein angiography, adverse events, and cost. Once the optimal monotherapy has been determined, we will proceed with the Combination Therapy Trial. The specific aim of this second study will be to determine the relative safety and efficacy of treatment with the best monotherapy (6MT) determined from the first trial versus several combination therapies as follows: 1) BMT alone, 2) BMT combined with photodynamic therapy with verteporfin, or 3) BMT combined with treatment with anecortave acetate. Treatments will be evaluated using the same criteria as the Monotherapy Trial. The results of these studies will hopefully improve the treatment of neovascular AMD. Reducing the number and type of treatments without compromising efficacy would reduce the treatment burden for patients as well as produce a potential cost reduction to Medicare of $4.62 billion per year. Combination therapies could further improve visual outcomes, reduce the number of treatments required, and increase cost savings. [unreadable] [unreadable] [unreadable] [unreadable]